Nuclear factor kappa B (NFκB) is a family of inducible transcription factors found virtually ubiquitously in all cells. NFκB can be activated in response to a wide array of harmful cellular stimuli, including cytokines, bacterial lipopolysaccharide, viral infection, phorbol esters, ultraviolet radiation, and free radicals (Baldwin, Ann. Rev. Immunol. 1996, 14, 649-681). NFκB has been implicated in a variety of human diseases and disorders, including inflammation, asthma, atherosclerosis, viral infections, septic shock, arthritis, autoimmune diseases, and cancer (Baldwin, Ann. Rev. Immunol. 1996, 14, 649-681; Baeuerle et al., Cell 1996, 87, 13-20; Stancovski et al., Cell, 1997, 91, 299-302). For example, NFκB is activated in arthritic synovium (Yang et al., FEBS Letts. 1995, 361, 89-96; and Baldwin, Ann. Rev. Immunol. 1996, 14, 649-681). Cyclooxygenase-2, an inducible enzyme regulated by NFκB, is responsible for the increased production of prostaglandins and thromboxane in inflammatory disease (Yamamoto et al., J. Biol. Chem. 1995, 270, 31315-31350; Crofford et al., J. Clin. Invest. 1994, 93, 1095-1101). Therefore, there exists a need for therapies to modulate the cellular functions of NFκB.
Polycystic kidney disease (PKD) is the most common life-threatening genetic disease, affecting more than 600,000 Americans and an estimated 12.5 million people worldwide. PKD is characterized by the presence of fluid-filled cysts in the kidneys, often resulting in renal failure. About 50 percent of patients with PKD will have kidney failure by age 60 and about 60 percent will have kidney failure by age 70. Although kidneys usually are the most severely affected organs, PKD can cause cysts to develop in the liver and elsewhere in the body. Liver cystogenesis occurs in more that 95% of PKD patients.
Autosomal dominant PKD (ADPKD) and autosomal recessive PKD (ARPKD) are the most common forms of PKD. Harris et al., Annu. Rev. Med. 2009, 60, 321-337. ADPKD is passed from a parent to a child by an autosomal dominant type of inheritance. Thus, only one copy of the abnormal gene is needed to cause the disease. ADPKD is caused by mutations in PKD1 (encoding polycystin-1), PKD2 (encoding polycystin-2), and/or PKD3 (unmapped). Harris et al., Annu. Rev. Med. 2009, 60, 321-337; Hughes et al., Nature Genetics 1995, 10, 151-160; Mochizuki et al., Science 1996, 272, 1339-1342; Koptides et al., Hum. Genet. 2000, 107, 115-126. Polycystin-1 is a membrane receptor capable of binding and interacting with many proteins, carbohydrates, and lipids, and eliciting intracellular responses through phosphorylation pathways, whereas polycystin-2 is thought to act as a calcium-permeable channel. Polycystins regulate tubular and vascular development in the kidneys and in other organs, including the liver, brain, arterial blood vessels, and pancreas, causing extra-renal manifestations of the disease.
ARPKD is the most common genetic cystic renal disease occurring in infancy and childhood. ARPKD is passed by an autosomal recessive pattern of inheritance. Thus, both parents must carry the abnormal gene, and both must pass the gene to the child in order for the child to develop the disease. ARPKD is caused by mutations in PKHD1 (encoding fibrocystin). Harris et al., Annu. Rev. Med. 2009, 60, 321-337; Ward et al., Nature Genetics. 2002, 30, 259-269. Fibrocystin has been found in the same complex as polycystin-2. However, the precise function of fibrocystin is at present unknown, but it may mediate its activity through polycystin-2. Harris et al., Annu. Rev. Med. 2009, 60, 321-337.
Other polycystic diseases include polycystic liver disease (PLD), polycystic pancreas disease (PPD), and polycystic ovarian syndrome (PCOS). Abdul-Majeed et al., Obstet. Gynecol. Int. 2011, Epub 2011. PLD is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD occurs isolated in the liver or in combination with PKD. Though cystic liver is one of the most common extrarenal manifestations observed in PKD, it also exists as an isolated inherited cystic disease without any kidney cysts. Qian, Adv. Chronic Kidney Dis. 2010, 17, 181-189. Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Qian et al., Hepatology 2003, 37, 164-171; Reces et al., World J. Gastroenterol. 2005, 11, 7690-7693. PLD is genetically heterogeneous, all being transmitted autosomally in a dominant or recessive fashion. PLD is caused by mutations in PPRKCSH or SEC63. Davila et al., Nature Genetics 2004, 36, 575-577; Waanders et al., Hum. Mutat. 2006, 27, 830. PPRKCSH encodes the noncatalytic β-subunit of glucosidase II (GIIβ) involved in the folding of glycoproteins, whereas SEC63 encodes a protein involved in protein trafficking in the ER. Fedeles et al., Nature Genetics 2011, 43, 639-647; Muller et al., FEBS Lett. 2011, 585, 596-600; Qian, Adv. Chronic Kidney Dis. 2010, 17, 181-189.
Currently, there is no approved treatment for polycystic diseases to halt cyst growth. For example, the management for PKD and PLD is centered on palliating symptoms and treating complications. Qian, Adv. Chronic Kidney Dis. 2010, 17, 181-189. Therefore, there is a need for an effective method for the treatment of a polycystic disease.